Title:  Sustained release theophylline formulations, excipient systems and methods of production

United States Patent:  6,171,615

Assignee:  Gattefosse (Saint Priest, FR); SmithKline Beecham Corp. (Philadelphia, PA)

Filed:  July 6, 1998

A stable sustained release theophylline formulation is prepared by incorporating theophylline into a semi-solid matrix comprising polyglycolized glycerides (GELUCIRE.RTM. excipient) and a mixture of nucleation enhancers. Theophylline is admixed with molten GELUCIRE to make the sustained release formulation. The nucleation enhancer composition is then incorporated in the admixture to make the sustained release formulation resistant to changes in dissolution upon aging. Orally administrable compositions are prepared by filling gelatin capsules with the formulation. The polyglycolized glycerides (GELUCIRE) and the nucleation enhancer composition also can be used as an excipient system for preparing sustained release pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of therapeutically effective, orally administrable, sustained release compositions of theophylline has been complicated because of problems associated with dissolution upon ageing. In some cases, when GELUCIRE based matrices are not effectively stabilized, the drug will dissolve more quickly after ageing due to a change in the physical structure and morphology of the material. We have now discovered that the use of a nucleation enhancer composition added to GELUCIRE 50/13 excipient can be used effectively to inhibit physical changes of GELUCIRE 50/13 and consequently decrease significantly dissolution changes upon ageing of highly water soluble pharmaceutical agents such as theophylline, particularly theophylline itself, and to prepare compositions for use in sustained release gelatin capsules.

The nucleation enhancer composition is comprised of glyceryl monostearate (GMS) and polyethylene glycol (PEG) having a number average molecular weight (abbreviated herein as "PM") of from about 1,000 to about 2,000, preferably about 1300-1600 and most preferably about 1450. The ratio of PEG to GMS in the composition can be varied from about 1:2 to about 2:1 and excellent results have been obtained when the ratio is from about 1.2:1 to about 1:1.2. The nucleation enhancer composition is employed in amounts from about 5% to about 50% by weight, preferably from about 5% to about 10% by weight of the GELUCIRE composition.

GELUCIRE compositions are inert semi-solid waxy materials which are amphiphilic in character and are available with varying physical characteristics. They are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value. The melting point is expressed in degrees Celsius and the HLB (Hydrophile-Lipophile Balance) is a numerical scale extending from 0 to approximately 20. Lower HLB values denote more lipophilic and hydrophobic substances, and higher values denote more hydrophilic and lipophobic substances. The affinity of a compound for water or for oily substances is determined and its HLB value is assigned experimentally. One or a mixture of different grades of GELUCIRE excipient may be chosen to achieve the desired characteristics of melting point and/or HLB value.

As to the chemistry of GELUCIRE 50/13 compositions, they are polyglycolized glycerides that are prepared by the alcoholysis reaction of natural oils with polyethylene glycols (PEG). They are mixtures of monoesters, diesters and/or triesters of glycerides of long chain (C₁₂ to C₁₈) fatty acids, and PEG (mono- and/or di-) esters of long chain (C₁₂ to C₁₈) fatty acids and can include free PEG. GELUCIRE compositions are generally described herein as fatty acid esters of glycerol and PEG esters or as polyglycolized glycerides.

The large family of GELUCIRE compositions is characterized by a wide range of melting points of from about 33^oC to about 64^oC and most commonly from about 35^oC to about 55^oC, and by a variety of HLB values of from about 1 to about 14, most commonly from about 7 to about 14. For example, GELUCIRE 50/13 designates a melting point of approximately 50^oC and an HLB value of about 13 to this grade of GELUCIRE. The appropriate choice of melting point/HLB value of a GELUCIRE or a mixture of GELUCIRE compositions will provide the delivery characteristics needed for a specific function, e.g., immediate release, sustained release, and the like. The low melting points of many of the solid GELUCIRE compositions provide a means of incorporating the pharmaceutically active ingredients in them at temperatures from about 0^oC to about 50^oC above their respective melting points, and then filling the melt (solution and/or dispersion) in hard gelatin capsules. The melt solidifies inside the capsules upon cooling to room temperature.

GELUCIRE 50/13 and GELUCIRE 53/10 can be used according to our invention, but GELUCIRE 50/13 has been found to be particularly effective. It is composed of fatty acid (majority of C₁₆ and C₁₈) esters of glycerol, PEG esters and free PEG.

According to the U.S. Pharmacopeia (USP) theophylline can be used as a bronchodilator for treatment of symptomas from asthma in chronic bronchitis and emphysema. The present invention is concerned with the oral administration of theophylline in therapeutically effective amounts (known to those skilled in the art) and in a sustained release oral dosage form.

The process of the invention requires melting the GELUCIRE and heating the molten GELUCIRE at a temperature from about 5^oC to about 50^oC above its melting point while stirring. For GELUCIRE 50/13, heating is at a temperature from about 55^oC to about 100^oC, preferably from about 65^oC to about 75^oC The pharmaceutical agent then is admixed with the molten GELUCIRE to make a first admixture. The temperature is maintained during and following admixing, and stirring of the first admixture is continued for a sufficient amount of time to ensure that the admixture is homogeneous. The amount of time required to attain homogeneity will be apparent to those skilled in the art and for theophylline admixed with GELUCIRE 50/13 on a laboratory scale the time required was from 10 to 30 minutes.

The nucleation enhancer composition then is admixed with the first homogeneous admixture while maintaining heating at about 65^oC to make a second admixture. Stirring of the second admixture is continued for a sufficient amount of time at about 65^oC, to ensure that the admixture is homogeneous, thus making a second homogeneous admixture. The amount of time required to attain homogeneity will be apparent to those skilled in the art and for theophylline admixed with GELUCIRE 50/13 and a nucleation enhancer composition comprised of PEG 1450 and GMS the time on a laboratory scale is from about 1 to about 15 minutes.

We have unexpectedly found that the sequence of steps is important in that the nucleation enhancer must be added after the GELUCIRE is admixed with the pharmaceutically active agent in order to attain the desired sustained release properties of the invention.

The second homogeneous admixture is then filled into hard gelatin capsules. Heating and mixing is continued up to the time the capsules are filled and after the capsules are filled they are allowed to return to ambient temperature.

In a formulation comprising 40% theophylline and 60% of a mixture containing 90% GELUCIRE, 5% GMS and 5% PEG 1450, the following is an example of a process that has been used successfully:

1. Melt 47.25 g of GELUCIRE 50/13 in a beaker on a heating plate to 65^oC with stirring.

2. Add 35 g of theophylline and wait for 30 minutes to make sure the mixture is homogenous. The heating temperature is still 65^oC.

3. Add 2.62 g of solid GMS and 2.62 g of solid PEG 1450 at the same time in the mixture, with stirring.

4. Wait for 5 to 10 minutes to obtain a homogenous mixture.

5. Fill the capsules with about 300 mg of the mixture.

6. Maintain capsules at ambient temperature for about 8 hours to allow solidification and thermal equilibrium.

The invention can comprise, consist essentially of or consist of polyglycolized glycerides, a nucleation enhancer composition and theophylline, as described herein, and the nucleation enhancer composition can comprise, consist essentially of or consist of glyceride monostearate and polyethylene glycol, as described herein.

Claim 1 of 6 Claims

What is claimed is:

1. A sustained release theophylline formulation in capsule unit dosage form comprising a gelatin capsule containing a semi-solid matrix, said semi-solid matrix consisting essentially of polyglycolized glycerides, a nucleation enhancer composition consisting essentially of glyceryl mono stearate and polyethylene glycol, and a therapeutically effective amount of theophylline.

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